Development of a new immunosuppressive strategy by targeting pyrimidine synthesis
| Project/Area Number |
15390388
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Hokkaido University |
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Principal Investigator |
SHIMAMURA Tsuyoshi (2004) Hokkaido University Hospital, Assistant Prof., 病院, 助教授 (00333617)
陳 孟鳳 (2003) 北海道大学, 大学院・医学研究科, 寄附講座教員 (40333603)
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| Co-Investigator(Kenkyū-buntansha) |
FURUKAWA Hiroyuki Hokkaido Univ., School of Med., Prof., 大学院・医学研究科, 寄附講座教員 (70292026)
TODO Satoru Hokkaido Univ., School of Med., Prof., 大学院・医学研究科, 教授 (60136463)
嶋村 剛 北海道大学, 医学部・歯学部付属病院, 助手 (00333617)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥11,800,000 (Direct Cost: ¥11,800,000)
Fiscal Year 2004: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2003: ¥7,000,000 (Direct Cost: ¥7,000,000)
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| Keywords | FK778 / FK779 / New immunosuppxessants / Tacrolimus / Cyclosporin / Organ transplantation / Pyrimidine synthesis / Resection / 異種移植 / Costimulation / leflunomide / タクロリムス / サイクロスポリン |
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| Research Abstract |
Leflunomide is a strong immunosuppressant that exerts its effect by blocking de novo pyrimidine synthesis. It has been shown that Leflunomide is a useful immunosuppressive agent in clinical trials of autoimmune diseases. However, due to the drug's long half-life, Leflunomide has never been clinically applied in the field of organ transplantation. A new Leflunomide derivative, FK778 and FK779, that has a shorter half-life than its mother drug were developed to resolve such problem. In this study, we have examined immunosuppressive effect, pharmacokinetics and side-effects of FK778 and FK779 in rat heart transplantation and dog kidney transplantation. In addition, we assessed immunosuppressive effect of FK778 and FK779 in combination with calcineurin inhibitors, tacrolimus (TAC) and cydosporine (CsA). In both rat and dog transplantation models, FK778 and/or FK779 prolonged allograft survival Also, there was an additive or synergistic effect when given with these calcineurin inhibitors. In a dog transplantation model, a slight leukocytopenia and anemia was observed when FK778 was administered at 6 mg/kg/day ; however, no serious side-effect was noted. We further examined an immunosuppressive effect of FK779 in a hamster-to-rat heart xenotransplantation model. FK779 effectively controlled both acute vascular and acute cellular xenograft rejections and markedly prolonged xenograft survival when combined with calcineurin inhibitors (TAC/CsA) or CD40-CD154/B7-CD28 costimulation blockades. We conclude that FK778 and FK779 are powerful and useful immunosuppressant that has a potential for clinical application in organ transplantation.
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Report
(3 results)
Research Products
(4 results)
